The overall objective of this proposal is to examine the molecular organization of the opiate and muscarinic receptor of brain as part of an effort to understand the mechanism of action of two drugs of abuse: the opiate narcotics and anticholinergic hallucinogens. We have proposed that phosphatidylserine (PS) may be an integral component of the opiate receptor, and further efforts will be made to verify this through the use of PS-decarboxylase and phospholipase A2 as well as by reconstitution with added PS. A number of autolytic peptides of trypsin and chymotrupsin having an affinity for the opiate receptor are to be isolated and further characterized chemically as well as pharmacologically. Studies will be undertaken to investigate the molecular characteristics of the brain muscarinic cholinergic receptor, particularly with regard to the factor associated with its interconversion from an antagonist to an agonist-preferred state. The phospholipid requirements of the muscarinic receptor will be investigated in relation to their multiconfigurational states. Chemical modifying agents and transition metals will be examined for their ability to influence stereospecific and specific antagonist and agonist-binding. With the use of affinity columns prepared by attaching high affinity ligands to sepharose, attempts will be made to purify and isolate both the opiate and muscarinic receptors from mammalian brain.